tbuckley/cabot-search huggingface dataset:
Abstract 5988: Intra-carotid artery brain metastasis models for evaluation of lung and breast cancer drugs
Authors: Fuyang Wang, Yuying Yang, Haoxia Zhao, Chunlei Dai, Bingrui Han, Mengyao Zhang, Xia Xiong, Chao Zhang, Xuzhen Tang, Qunsheng Ji
Journal: Cancer Research (2022)

Abstract Non-CNS metastatic brain cancer is about 10 times more common than CNS cancer. Lung cancer and breast cancer account for most brain metastasis. KRAS-mutant NSCLC compose a third lung adenocarcinoma, among which 17% to 55% will develop brain metastases. Likewise, more than a third HER2-positive breast cancer will develop brain metastasis. Among existing animal models, the ectopic injection in brain cannot reflect the mechanism of tumor invasion and metastasis, while tail vein and intra-cardiac injection usually produces extra-cerebral metastatic disease and the animals have to be sacrificed before brain metastases appeared. Here we developed several metastasis models injected by intra-carotid artery (ICA) to address these problems. Two KRAS-mutant lung cancer cells and two HER2-positive breast cancer cells selected by their metastasize potential were luciferase labeled for in vivo imaging and drug evaluation. The tumor pathology in brain was evaluated by H&amp;E staining. Compared to ectopic models, these ICA models have natural dissemination and progression in the brain, which recapitulate the different pattern of metastatic lesions in the clinic. With synchronized growth rate and little variation compared to tail vein and intra-cardiac models, these tumor growth kinetics allow for more appropriate animal efficacy study. Both KRAS-sensitive and insensitive models have been developed and validated for the next generation drug development; HER-2 positive breast models with ICA method also showed a good discriminative power on anti-HER2 modalities including antibodies, small molecules and ADC. Meanwhile, ICA models with human immune cell reconstitution were also developed to support immune therapies in pre-clinical stage. In summary, we have developed a panel of intra-carotid artery brain metastatic models for drug evaluation, and demonstrated their superiority in growth kinetics, brain microenvironment, drug selectivity and immune component. These models can be a promising predictive tool for novel drug/modality discovery to target brain metastasis. Citation Format: Fuyang Wang, Yuying Yang, Haoxia Zhao, Chunlei Dai, Bingrui Han, Mengyao Zhang, Xia Xiong, Chao Zhang, Xuzhen Tang, Qunsheng Ji. Intra-carotid artery brain metastasis models for evaluation of lung and breast cancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5988.
Abstract 894: CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma
Authors: Caitlin Molczyk, Elizabeth Thomas, Lubaba Zaman, Paran Goel, Rakesh K. Singh
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Often diagnosed late in disease progression, PDAC is notorious for chemotherapy resistance as well as having metastases. A cell population of interest aiding in this progression is the cancer stem cell (CSC). These cells are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Previous studies have determined CXCR4, ALDH1, CD24, CD44, and CD133 are markers of PDAC CSCs. In the present study, we investigated CXCR1 as a marker and therapeutic target for PDAC CSCs. CXCR1 is a G-coupled transmembrane protein receptor with downstream effects known to aid in anti-apoptosis, proliferation, and angiogenesis via binding CXCL8 and CXCL6. Already known to be a CSC marker and target in triple-negative breast cancer, initial studies by Chen et al. of CXCR1 in PDAC demonstrate CXCL8 induces increased tumorsphere formation in vitro, leading us to investigate CXCR1 in PDAC CSCs. Considering these findings, we hypothesized that PDAC cells with high CXCR1 activity exhibit increased CSC-like characteristics, and targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in PDAC CSC-like phenotype, we used two PDAC cell lines, CD18/HPAF and T3M4, and developed gemcitabine resistant (GemR) counterparts. These GemR cell lines were shown to have over 10-fold higher resistance than their respective parent cell lines. We treated with the CXCR1/2 antagonist navarixin at concentrations known to inhibit CXCR1. Using the parent cell lines’ relative IC50 concentrations for each drug, we treated cells for 72 hours. We used qRT-PCR and ELISAs for analysis of several known CSC markers and CXCR1 axis expression. From our results, we see the beginning trends of GemR cells having increased expression of CSC markers as well as gemcitabine-treated parent and resistant cells having increased expression. Using flow cytometry, we evaluated the CXCR1+ cell populations post-control and gemcitabine treatment. The population of CXCR1+ cells was higher in the gemcitabine-treated groups. Together, our observations suggest an association between CXCR1 and the CSC-like phenotype in PDAC. Citation Format: Caitlin Molczyk, Elizabeth Thomas, Lubaba Zaman, Paran Goel, Rakesh K. Singh. CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 894.
The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate Cancer
Authors: Goutam Chakraborty, Subhiksha Nandakumar, Rahim Hirani, Bastien Nguyen, Konrad H. Stopsack, Christoph Kreitzer, Sai Harisha Rajanala, Romina Ghale, Ying Z. Mazzu, Naga Vara Kishore Pillarsetty, Gwo-Shu Mary Lee, Howard I. Scher, Michael J. Morris, Tiffany Traina, Pedram Razavi, Wassim Abida, Jeremy C. Durack, Stephen B. Solomon, Matthew G. Vander Heiden, Lorelei A. Mucci, Andreas G. Wibmer, Nikolaus Schultz, Philip W. Kantoff
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Oncogenic alterations of the PI3K/AKT pathway occur in &amp;gt;40% of patients with metastatic castration-resistant prostate cancer, predominantly via PTEN loss. The significance of other PI3K pathway components in prostate cancer is largely unknown. Experimental Design: Patients in this study underwent tumor sequencing using the MSK-IMPACT clinical assay to capture single-nucleotide variants, insertions, and deletions; copy-number alterations; and structural rearrangements, or were profiled through The Cancer Genome Atlas. The association between PIK3R1 alteration/expression and survival was evaluated using univariable and multivariable Cox proportional-hazards regression models. We used the siRNA-based knockdown of PIK3R1 for functional studies. FDG-PET/CT examinations were performed with a hybrid positron emission tomography (PET)/CT scanner for some prostate cancer patients in the MSK-IMPACT cohort. Results: Analyzing 1,417 human prostate cancers, we found a significant enrichment of PIK3R1 alterations in metastatic cancers compared with primary cancers. PIK3R1 alterations or reduced mRNA expression tended to be associated with worse clinical outcomes in prostate cancer, particularly in primary disease, as well as in breast, gastric, and several other cancers. In prostate cancer cell lines, PIK3R1 knockdown resulted in increased cell proliferation and AKT activity, including insulin-stimulated AKT activity. In cell lines and organoids, PIK3R1 loss/mutation was associated with increased sensitivity to AKT inhibitors. PIK3R1-altered patient prostate tumors had increased uptake of the glucose analogue 18F-fluorodeoxyglucose in PET imaging, suggesting increased glycolysis. Conclusions: Our findings describe a novel genomic feature in metastatic prostate cancer and suggest that PIK3R1 alteration may be a key event for insulin–PI3K–glycolytic pathway regulation in prostate cancer.
Abstract 1694: Cytotoxic conditions alter cell free DNA concentration and fragment size in cancer cells
Authors: Prisca Bustamante, Thupten Tsering, Julia Valdemarin Burnier
Journal: Cancer Research (2022)

Abstract Introduction: Detection of circulating free DNA (cfDNA) is a promising tool to monitor and predict tumor progression and treatment efficacy. Our group has shown the clinical relevance of cfDNA as a biomarker of tumor development and progression in several cancer models, including colorectal carcinoma and melanoma. cfDNA may stem from a combination of apoptosis, necrosis, and cellular secretions. However, the source and mechanism of cfDNA release in cancer cells are still unclear. Indeed, while some data state that cfDNA is derived from apoptosis, other studies report it is mainly a product of cellular secretions. To better understand cfDNA release and its correlation with tumor biology, this study aimed to assess cfDNA kinetics under cell death, cell cycle arrest, and senescence by using an in vitro cancer model. Methods: Colorectal (HTC116 and HT29), lung (A549), and melanoma (MP41 and OMM2.5) cancer cells underwent cytotoxic conditions by drugs: TRIAL/APO2L, Roscovitine, and valproic acid (VAP), as well as environmental stress by heat and irradiation. Cell death and cell cycle were evaluated by FACS. β-galactosidase staining assessed senescence. cfDNA was extracted from 3 mL supernatant using QIAamp nucleic acid kit and evaluated by digital droplet PCR through hot spot mutations (Mut), and a mitochondrial gene (mt-cfDNA). Isolated cfDNA was visualized by fragment size using Bioanalyzer 2100. Results: Mut and mt-cfDNA increased during cytotoxic conditions in a dose-dependent manner. Cells under apoptosis released greater mut and mt-cfDNA compared to necrotic and untreated cells. Similarly, cell cycle disturbances by VAP were associated with an increase in Mut and mt-cfDNA. Moreover, β-galactosidase positive cells (5D post-irradiation) showed lower Mut and mt-cfDNA levels than control conditions. Electropherogram images showed that cytotoxic conditions alter fragment size distribution. While fragments about 100-200 bp were observed in apoptosis, necrosis showed more abundant fragments about &amp;gt;1000 bp. Conclusions: The release of cfDNA is influenced by cytotoxic and stress conditions. Knowing the biology of cfDNA can help understand its role in cancer development and how best to utilize this marker clinically, especially post cytotoxic agents that induce different cell death mechanisms. These findings have major implications in the interpretation of ctDNA in liquid biopsy as a biomarker of treatment response and tumor progression. Citation Format: Prisca Bustamante, Thupten Tsering, Julia Valdemarin Burnier. Cytotoxic conditions alter cell free DNA concentration and fragment size in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1694.
Abstract 1665: Humanized mice for preclinical efficacy evaluation of drugs targeting CD73
Authors: Xing Liu, Cunxiang Ju, Hongyan Sun, Jing Zhao, Xiang Gao, Zhiying Li
Journal: Cancer Research (2022)

Abstract CD73 expressed in Treg surface facilities the hydrolysis of AMP into adenosine which inhibits the activation, expansion and homing of T effector cells.Therapeutic efficiency of CD73 mAb had been studied in C57BL/6 and BALB/C mice xenografted with several murine cancer cell lines. However, for human CD73 mAb with no binding to murine CD73, CD73 humanized mouse models are essential for medicinal development.We established CD73 humanized mouse model (hCD73) on C57BL/6 and BALB/c background in which the mCD73 was replaced with hCD73. Similar expression level of hCD73 in peripheral blood was observed compared with mCD73 in wildtype mice. Besides, the proportion of T, B and NK cells in spleen of hCD73 mice were also analogy to that in wildtype mice. After treating with anti-hCD73 antibody, tumor growth was inhibited in our CT-26-hCD73 tumor model.Furthermore, hPD1/hPDL1/hCD73 mouse models were also established on C57BL/6 and BALB/c backgrounds based on hCD73 mice. However, a better anti-tumor effect of anti-CD73 antibody was found on BALB/c-hPD1/hPDL1/hCD73 bearing CT26 than that on B6-hPD1/hPDL1/hCD73 bearing MC38. Besides, Combination of anti-CD73 and anti-PD1 significant elevated anti-tumor effect comparing with anti-CD73 and anti-PD1 mono therapy in BALB/c-hPD1/hPDL1/hCD73 mice bearing CT26-hPDL1hCD73.In conclusion, BALB/c-hPD1/hPDL1/hCD73 is a well efficient mouse model for therapeutic effect study of anti-CD73 and relevant combination therapy. Citation Format: Xing Liu, Cunxiang Ju, Hongyan Sun, Jing Zhao, Xiang Gao, Zhiying Li. Humanized mice for preclinical efficacy evaluation of drugs targeting CD73 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1665.
AP-1 activation mediates post-natal cardiomyocyte maturation
Authors: Hongjie Zhang, Lijuan Pei, Zhaohui Ouyang, Haocun Wang, Xin Chen, Kai Jiang, Shiqi Huang, Rui Jiang, Yaozu Xiang, Ke Wei
Journal: Cardiovascular Research (2022)

Abstract Aims Post-natal maturation of mammalian cardiomyocytes proceeds rapidly after birth, with most of the myocytes exiting cell cycle, becoming binucleated, and adopting oxidative phosphorylation as the primary metabolic route. The triggers and transcriptional programmes regulating cardiomyocyte maturation have not been fully understood yet. We performed single-cell RNA-Seq in post-natal rat hearts in order to identify the important factors for this process. Methods and results Single-cell RNA-Seq profiling was performed of post-natal Day 1 and Day 7 rat hearts, and we found that members of the activating protein 1 (AP-1) transcription factors showed a transient up-regulation in the maturing cardiomyocytes, suggesting their functional involvement in the process. Activating members of the AP-1 family by palmitate or adrenergic stimulation inhibited cardiomyocyte cytokinesis and promoted cardiomyocyte maturation. In contrast, knocking down AP-1 members Atf3 and Jun promoted cardiomyocyte cytokinesis, reduced polyploidy, and inhibited maturation. Mechanistically, RNA-Seq results and rescue experiments indicated that AP-1 members activate the expression of fatty acid metabolic genes to promote cardiomyocyte maturation. Finally, intraperitoneal injection of AP-1 inhibitor T-5224 in neonatal mice inhibits cardiomyocyte maturation in vivo. Conclusion Our results are the first evidence implicating AP-1 transcription factors in post-natal cardiomyocyte maturation both in vitro and in vivo, which expand our understanding of the molecular mechanism of cardiomyocyte maturation, and may lead to novel therapies to treat congenital heart diseases.
Abstract 3167: The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth
Authors: Somanath Kundu, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, Mariano S. Viapiano
Journal: Cancer Research (2022)

Abstract Proteins complexes that maintain the apico-basal polarity of epithelial cells and organize cell-signaling domains are necessary for normal tissue organization and therefore regarded as tumor suppressors. Accordingly, the scaffolding proteins that form the Scribble polarity complex (SCRIB, LLGL1, and DLG members) are usually downregulated in cancer, in particular in highly aggressive or invasive tumors. Because gliomas arise from non-epithelial precursors that are likely motile before transformation, the expression and functions of these scaffolding proteins in malignant brain tumors has remained almost entirely unexplored. Surprisingly, we have found that one member of the DLG family, DLG5, is highly upregulated in malignant gliomas compared to other solid tumors. Indeed, DLG5 was the predominant DLG member found in all molecular subtypes of glioblastoma (GBM). Knockdown of DLG5 reduced the viability, invasiveness, and self-renewal of GBM stem cells belonging to the proneural and mesenchymal molecular subtypes. As a result, intracranial tumors defficient in DLG5 were smaller and less proliferative than controls, resulting in extended animal survival. At the molecular level, DLG5 knockdown decreased the expression of stemness-related genes (SOX2, NANOG, POU5F1) but increased the expression of LLGL1, a component of the Scribble complex that is associated with neural precursor differentiation. These changes were accompanied by downregulation of Sonic Hedgehog (SHh) signaling, both in vitro and in vivo, which drives GBM cell stemness and proliferation. Moreover, DLG5-deficient GBM stem cells became insensitive to exogenous SHh and were unable to upregulate Gli1 or increase cell invasion in presence of added SHh, compared to control cells. We further confirmed that DLG5 downregulation increased the ubiquitination of Gli1-containing complexes as well as Gli1 proteasomal degradation, providing a suitable mechanism for the loss of SHh signaling and tumor stemness. These results describe for the first time the expression of a DLG family member in malignant gliomas and reveal a novel, polarity-independent, pro-tumoral function of DLG5, which differs from its proposed tumor-suppressor role in other solid tumors. Citation Format: Somanath Kundu, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Shawn Rai, Lawrence S. Chin, Timothy E. Richardson, Mariano S. Viapiano. The scaffolding protein DLG5 is necessary to maintain Sonic Hedgehog signaling in glioblastoma stem cells and promote tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3167.
Abstract 1505: Exploring the role of CRM1 in DNA repair pathway in prostate cancer cells
Authors: Rajendra Kumar, Janet Mendonca, Kavya Boyapati, Yuhan Yang, Deven Topiwala, Suthicha Kanacharoen, Keerti Soundappan, Lillian Wilson, Eleni Panagopoulos, Michael Carducci, Sushant K. Kachhap
Journal: Cancer Research (2022)

Abstract Background: Prostate cancer continues to show challenges in disease management and ultimately leads to advanced disease with poor survival. These unmet needs, despite recent advances, are leading researchers to identify novel targets to develop next-generation therapeutics. Considerable evidence from the published reports and TCGA database analysis indicates that CRM1, which functions as a nuclear export protein, amplifies prostate cancer, resulting in dysregulated nuclear export machinery. This dysregulation is also seen to correlate with mislocalization of p53, FOXO-1, and 3a, cyclinD1, p16, p21, and p27 in prostate cancer. Besides these mislocalized proteins, key DNA repair pathway members such as BRCA1 and Rad51 exhibit a nuclear export signal (NES) and are putative CRM1 cargoes. Nuclear-cytoplasmic shuttling of these repair proteins may play an essential role in repairing damaged DNA. We hypothesize that inhibition of CRM1 would result in defective DNA repair through disruption of nuclear-cytoplasmic shuttling of important repair protein cargoes. Methods: PCa cells (both AR-positive and negative lines) were treated with Selinexor to estimate the subtoxic doses. Cell lysates and total mRNA were collected to evaluate the relative levels of BRCA-1, RAD51, p53, ATM, ATR transcripts, and proteins. Activation of the DNA damage pathway was measured through a phosphorylated form of these proteins, and functional assessment of homologous recombination(HR) was measured through an HR sensor plasmid construct. Results: Treatment of PCa cells with Selinexor affected expression, localization, and kinetics of DNA repair leading to unrepaired DNA and induced apoptosis. Citation Format: Rajendra Kumar, Janet Mendonca, Kavya Boyapati, Yuhan Yang, Deven Topiwala, Suthicha Kanacharoen, Keerti Soundappan, Lillian Wilson, Eleni Panagopoulos, Michael Carducci, Sushant K. Kachhap. Exploring the role of CRM1 in DNA repair pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1505.
Abstract 2607: Inhibition of HDAC3 induces BRCAness and potent synergy with PARP inhibition in neuroendocrine prostate and small cell lung cancers
Authors: Stephanie Nagl, Kendra Devore, Gregg Hirschfeld, Kari Kotlarczyk, Damaris Diaz, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately
Journal: Cancer Research (2022)

Abstract HDAC3 is essential for transcriptional repression and is required for the activity of NCOR1 &amp; SMRT co-repressors complexes. Inhibition of HDAC3 results in the suppression of genes responsible for DNA damage repair and maintenance of genomic stability. HDAC3/NCOR1 also play critical roles in tumor metabolism and immune cell biology. GB-3103 is a novel and potent inhibitor of HDAC3 with an IC50 of 0.56nM that was tested for activity against human neuroendocrine prostate (NEPC) and small cell lung cancers (SCLC). RNA-seq analysis of GB-3103 treated human tumor cells revealed induction of BRCAness, inhibition of genes from DNA repair pathways and inhibition of PI3K-AKT1, MYC and p53 signaling. GB-3103 showed potent in vitro anticancer activity against the human H660 NEPC line, with an IC50 of 28nM, and 21nM against the murine PNEC30 line and potent IC50 of 16nM against NCI-H209 human lung neuroendocrine cancer. Because of the potent induction of BRCAness we used zero interaction potency (ZIP) model to test the activity of the combination of GB-3103 with a PARP inhibitor against human H660 and murine PNEC30 cell lines. These experiments revealed synergy for the combination of PARPi with GB-3103 in NEPC. GB-3103 was subsequently tested alone and in combination with olaparib in a xenograft model of H660. GB3103 (TGI=3%) showed minimal activity at the selected dose against H660 compared to single agent olaparib (TGI=67%). However, when combined with olaparib, GB-3103 revealed potent synergy (TGI=96%, p&amp;lt;0.01). In the NCI-H209 human lung neuroendocrine xenograft model, GB-3103 showed robust activity as a single agent (TGI=83%) compared to single agent olaparib (TGI=33%) and single agent talazoparib (TGI=69%). When combined with olaparib, GB-3103 induced synergistic antitumor effect (TGI=99%, p&amp;lt;t0.001) when compared to olaparib treatment alone. When combined with talazoparib, GB-3103 induced synergistic antitumor effect (TGI &amp;gt;100%, p&amp;lt;0.001) when compared to talazoparib treatment alone. Taken together, these data confirm the important role of HDAC3 in neuroendocrine prostate and small cell lung cancers and suggest HDAC3 inhibition by GB-3103 could be an effective approach for patients with neuroendocrine cancers particularly when combined with inhibitors of PARP. Citation Format: Stephanie Nagl, Kendra Devore, Gregg Hirschfeld, Kari Kotlarczyk, Damaris Diaz, Tong Wang, Maggie Murray, Paul Gonzales, Stephen Thomas Gately. Inhibition of HDAC3 induces BRCAness and potent synergy with PARP inhibition in neuroendocrine prostate and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2607.